Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

The Department of Cancer BiologyContinued from Page 56in neuronal function, and studying them will aidour understanding of such disorders as stroke,pain, diabetic neuropathy, epilepsy, andamyotropic lateral sclerosis, as well asAlzheimer’s, Huntington’s, and Parkinson’sdisease.We have identified an enhancer region thatis responsible for the strong expression of PSMAin prostate cancer. We are using this enhancerregion for gene therapy approaches such asprodrug strategies using the nontoxic prodrug 5fluorocytosine (5FC). 5FC is converted by theenzyme cytosine deaminase to 5 fluorouracil(5FU), which is toxic to dividing cells. When wetransfect cells with expression vectors containingcytosine deaminase driven by the PSMApromoter/enhancer, following expression andtreatment with 5FC, we kill PSMA-expressingcancer cells but not non-PSMA-expressing tumorcells. This expression is enhanced with hormonedeprivation and is thus likely to provide a usefulstrategy, even when the prostate cancer patienthas been treated with hormones. We havegenerated mice in which green fluorescent protein(GFP) expression is being driven by the humanPSMA promoter/enhancer. Expression isobserved in the brain, kidney and testes, but onlyto a lesser extent in the prostate. The PSMApromoter/enhancer GFP reporter system will helpus model factors that effect tissue-specificexpression in vivo and identify factors responsiblefor the extremely high expression of humanPSMA in prostate.Prostate Cancer Program participants: The Prostate Cancer Program, comprised of a team of investigatorsfrom the Cleveland Clinic Glickman Urological Institute and the Lerner Research Institute, earned the first annualCleveland Clinic “Research Program of the Year” Award during 2002. The award honored the program that bestfulfilled the mission of the Programmatic Research Teams – to promote excellence through fully integrated scientific andeducational initiatives resulting from the collaborative efforts of basic and clinical researchers. Investigators contributingto the award winning prostate cancer research program are, from left, Howard Levin, M.D., Co-Director Skip Heston,Ph.D., Yan Xu, Ph.D., Robert Silverman, Ph.D., Graham Casey, Ph.D., Co-Director Eric Klein, M.D., AndreiGudkov, Ph.D., Raymond Tubbs, D.O., Jay Ciezki,. M.D., and Arul Mahadevan, M.D. Participants not picturedinclude Robert Dreicer, M.D., Tatiana Byzova, Ph.D., Ed Plow, Ph.D,.and Jennifer Brainard, M.D.57